Wang Jinghuan, Cheng Qianwen, Zhang Yuyu, Hong Chen, Liu Jiayao, Liu Xinhua, Chang Jun
Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Aging Dis. 2023 Aug 1;14(4):1458-1471. doi: 10.14336/AD.2023.0119.
The accumulation and deposition of beta-amyloid (Aβ) are key neuropathological hallmarks of Alzheimer's disease (AD). PARP16, a Poly(ADP-ribose) polymerase, is a known tail-anchored endoplasmic reticulum (ER) transmembrane protein that transduces ER stress during pathological processes. Here, we found that PARP16 was significantly increased in the hippocampi and cortices of APPswe/PS1dE9 (APP/PS1) mice and hippocampal neuronal HT22 cells exposed to Aβ, suggesting a positive correlation between the progression of AD pathology and the overexpression of PARP16. To define the effect of PARP16 on AD progression, adeno-associated virus mediated-PARP16 knockdown was used in APP/PS1 mice to investigate the role of PARP16 in spatial memory, amyloid burden, and neuroinflammation. Knockdown of PARP16 partly attenuated impaired spatial memory, as indicated by the Morris water maze test, and decreased amyloid deposition, neuronal apoptosis, and the production of inflammatory cytokines in the brains of APP/PS1 mice. In vitro experiments demonstrated that the knockdown of PARP16 expression rescued neuronal damage and ER stress triggered by Aβ. Furthermore, we discovered that intracellular PARP16 acts as an RNA-binding protein that regulates the mRNA stability of amyloid precursor protein (APP) and protects targeted APP from degradation, thereby increasing APP levels and AD pathology. Our findings revealed an unanticipated role of PARP16 in the pathogenesis of AD, and at least in part, its association with increased APP mRNA stability.
β-淀粉样蛋白（Aβ）的积累和沉积是阿尔茨海默病（AD）关键的神经病理学特征。聚（ADP-核糖）聚合酶PARP16是一种已知的尾锚型内质网（ER）跨膜蛋白，在病理过程中传导内质网应激。在此，我们发现PARP16在APPswe/PS1dE9（APP/PS1）小鼠的海马体和皮质以及暴露于Aβ的海马神经元HT22细胞中显著增加，这表明AD病理进展与PARP16的过表达之间存在正相关。为了确定PARP16对AD进展的影响，在APP/PS1小鼠中使用腺相关病毒介导的PARP16敲低来研究PARP16在空间记忆、淀粉样蛋白负荷和神经炎症中的作用。如莫里斯水迷宫试验所示，PARP16的敲低部分减轻了空间记忆受损，并减少了APP/PS1小鼠大脑中的淀粉样蛋白沉积、神经元凋亡和炎性细胞因子的产生。体外实验表明，PARP16表达的敲低挽救了由Aβ触发的神经元损伤和内质网应激。此外，我们发现细胞内PARP16作为一种RNA结合蛋白，调节淀粉样前体蛋白（APP）的mRNA稳定性，并保护靶向的APP不被降解，从而增加APP水平和AD病理。我们的研究结果揭示了PARP16在AD发病机制中意想不到的作用，至少部分与APP mRNA稳定性增加有关。
